A compartmental tissue culture system has been used to control neuronal activity, to measure the strength of synaptic connections between defined neuronal populations and test hypotheses as to the mechanisms involved in activity-dependent synaptic plasticity. Postsynaptic electrical activity, NMDA receptor activation and intracellular calcium levels interact in determining the long term changes in synaptic efficacy produced by chronic stimulation of synaptic inputs. Axonal outgrowth (growth cone activity) from DRG neurons is quickly blocked by electrical activation (phasic stimulation is more effective than tonic). With prolonged stimulation (hours), the growth cone can become accommodated and resume outgrowth. Electrical stimulation increases intracellular calcium in growing axons and their growth cones. The increase is transient and the calcium buffering capacity of axons appears to be regulated, in part, by electrical activity. BayK 8644 reliably augments high-voltage activated (HVA) calcium currents while omega-conotoxin produces a moderate decrease in these currents in cultured mouse spinal cord (SC) and DRG neurons. BayK 8644 augments synaptic interactions between these cell types in a minority of cases (no change in most), while omega-conotoxin is without detectable effect (omega-conotoxin eliminates synaptic transmission at the frog neuromuscular junction). Our results suggest a high degree of heterogeneity with regard to the calcium channels responsible for neurotransmitter release.